Intertwining DNA-RNA nanocapsules loaded with tumor neoantigens as synergistic nanovaccines for cancer immunotherapy

Abstract

Nanomedicines that co-deliver DNA, RNA, and peptide therapeutics are highly desirable yet remain underdeveloped for cancer theranostics. Herein, we report self-assembled intertwining DNA-RNA nanocapsules (iDR-NCs) that efficiently delivered synergistic DNA CpG and short hairpin RNA (shRNA) adjuvants, as well as tumor-specific peptide neoantigens into antigen presenting cells (APCs) in lymph nodes for cancer immunotherapy. These nanovaccines were prepared by (1) producing tandem CpG and shRNA via concurrent rolling circle replication and rolling circle transcription, (2) self-assembling CpG and shRNA into DNA-RNA microflowers, (3) shrinking microflowers into iDR-NCs using PEG-grafted cationic polypeptides, and (4) physically loading neoantigen into iDR-NCs. CpG and shRNA in iDR-NCs synergistically activate APCs for sustained antigen presentation. Remarkably, iDR-NC/neoantigen nanovaccines elicit 8-fold more frequent neoantigen-specific peripheral CD8 + T cells than CpG, induce T cell memory, and significantly inhibit the progression of neoantigen-specific colorectal tumors. Collectively, iDR-NCs represent potential DNA/RNA/peptide triple-co-delivery nanocarriers and synergistic tumor immunotherapeutic nanovaccines.

Cancer‐Targeting Nanoparticles for Combinatorial Nucleic Acid Delivery

“…As with other types of nanoparticles, NFs can be combined with other types of materials to take advantage of their different characteristics. For instance, Zhu et al designed intertwining DNA‐RNA nanocapsules (iDR‐NCs) to deliver DNA and RNA together for antitumor immunotherapy . They designed DNA with a CpG sequence to stimulate TLR9 and amplified this using RCR; an shRNA sequence targeting Stat3, which has immunosuppressive functions in the presence of tumors, was encoded in DNA and also amplified by rolling circle transcription (RCT) in the same pot to .…”

“…Finally, the authors complexed the iDR‐NCs with a tumor neoantigen, Adpkg. The resulting particle, consisting of 1) CpG‐rich DNA, 2) Stat3‐targeting shRNA, 3) a cationic polymer, and 4) a tumor antigen was able affect multiple aspects of the tumor immune environment simultaneously and lead to a durable, specific T cell‐mediated antitumor response ( Figure ) …”

“…These iDR‐NCs could then be delivered to APCs in lymph nodes as a vaccine to promote gene knockdown, immunostimulation, and a tumor‐specific response C). Reproduced with permission . Copyright 2017, Nature Research.…”

Nanoparticle‐Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions

“…This has been realized through co‐entrapment of isolated antigens and immunopotentiators within the same nanosystems such as hydrogel, liposome, nanosphere, inorganic nanosheet, and other versatile nanocapsule . Moreover, Zhu et al self‐assembled DNA‐RNA microflowers with DNA CpG and short hairpin RNA to activate immunostimulation and reverse T cell tolerance, respectively . Subsequently, the DNA‐RNA microflowers were shrunk through PEG‐grafted cationic polypeptides into nanostructures accompanied by hydrophobic neoantigens ( Figure ).…”

“…c) Quantification of secreted TNFα, IL‐6, and IL‐12p40 in DC2.4 cells under different treatments. Reproduced with permission . Copyright 2017, the Authors, Published by Springer Nature.…”